|
1
|
Zhang W, Hong X, Xiao Y, Wang H, Zeng X. Sorafenib resistance and therapeutic strategies in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2025; 1880:189310. [PMID: 40187502 DOI: 10.1016/j.bbcan.2025.189310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/30/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.
Collapse
Affiliation(s)
- Weijing Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
| | - Xuechuan Hong
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Yuling Xiao
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
| | - Xiaodong Zeng
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
| |
Collapse
|
|
2
|
Ma YN, Jiang XM, Hu XQ, Wang L, Gao JJ, Liu H, Qi FH, Song PP, Tang W. Cinobufacini Inhibits Survival and Metastasis of Hepatocellular Carcinoma via c-Met Signaling Pathway. Chin J Integr Med 2025; 31:311-325. [PMID: 39028451 DOI: 10.1007/s11655-024-4111-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2024] [Indexed: 07/20/2024]
Abstract
OBJECTIVE To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.
Collapse
Affiliation(s)
- Ya-Nan Ma
- Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, China
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Xue-Mei Jiang
- Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, China
| | - Xi-Qi Hu
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Ling Wang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Jian-Jun Gao
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong Province, 266021, China
| | - Hui Liu
- Central South University, Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, China
| | - Fang-Hua Qi
- Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
| | - Pei-Pei Song
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
| | - Wei Tang
- International Health Care Center, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| |
Collapse
|
|
3
|
Sun R, Wu C, Gou Y, Zhao Y, Huang P. Advancements in second-line treatment research for hepatocellular carcinoma. Clin Transl Oncol 2025; 27:837-857. [PMID: 39162977 DOI: 10.1007/s12094-024-03653-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.
Collapse
Affiliation(s)
- Ruirui Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Chenrui Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yang Gou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yaowu Zhao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Ping Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China.
| |
Collapse
|
|
4
|
Haga Y, Ray R, Ray RB. Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model. Mol Carcinog 2025; 64:72-82. [PMID: 39377735 DOI: 10.1002/mc.23827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 10/09/2024]
Abstract
The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.
Collapse
Affiliation(s)
- Yuki Haga
- Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
- Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA
| | - Ratna B Ray
- Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA
- Department of Pathology, Saint Louis University, St. Louis, Missouri, USA
| |
Collapse
|
|
5
|
Ainiwaer A, Cheng J, Lang R, Peng T, Bi X, Lu Y, Chinese Research Hospital Association Society for Molecular Diagnosis, Translational Medicine Branch, China Association of Gerontology and Geriatrics. Chinese expert consensus on the clinical application of molecular diagnostics in hepatobiliary cancers (2024 edition). LIVER RESEARCH (BEIJING, CHINA) 2024; 8:195-206. [PMID: 39958921 PMCID: PMC11771259 DOI: 10.1016/j.livres.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/23/2024] [Accepted: 11/26/2024] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) are significant health challenges in China because of their high prevalence and mortality rates. Advances in molecular diagnostics have opened new avenues for personalized treatment strategies. This consensus provides a comprehensive update on the clinical applications of molecular diagnostics in HCC and BTC and addresses the urgent need for personalized treatment strategies tailored to the Chinese population, emphasizing the importance of molecular markers in guiding targeted therapies and immunotherapies. By employing the Delphi method and the Grading of Recommendations Assessment, Development, and Evaluation system, the expert panel formulated evidence-based recommendations for the use of molecular diagnostics in the clinical management of HCC and BTC. Key molecular markers, such as isocitrate dehydrogenase (IDH) 1 and 2, fibroblast growth factor receptor 2 (FGFR2), BRAF V600E, human epidermal growth factor receptor 2 (HER2), rearranged during transfection (RET), and neurotrophic tyrosine receptor kinase (NTRK), are highlighted for their roles in optimizing treatment regimens. The consensus also explores the significance of emerging biomarkers, such as tumor mutation burden and microsatellite instability, in predicting responses to immune checkpoint inhibitors. The recommendations aim to enhance precision medicine approaches, improve patient outcomes, and foster the integration of molecular diagnostics into routine clinical practice.
Collapse
Affiliation(s)
- Aizier Ainiwaer
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jiamin Cheng
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yinying Lu
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Chinese Research Hospital Association Society for Molecular Diagnosis
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Translational Medicine Branch, China Association of Gerontology and Geriatrics
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
6
|
Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
Collapse
Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
| |
Collapse
|
|
7
|
Dong H, Zhang Z, Ni M, Xu X, Luo Y, Wang Y, Zhang H, Chen J. The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy. Curr Treat Options Oncol 2024; 25:1239-1256. [PMID: 39259476 PMCID: PMC11485193 DOI: 10.1007/s11864-024-01246-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2024] [Indexed: 09/13/2024]
Abstract
OPINION STATEMENT Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.
Collapse
Affiliation(s)
- Heng Dong
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Zhengguo Zhang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Mengjie Ni
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Xiaoyun Xu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Yifeng Luo
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Yaru Wang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Haiyun Zhang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Jianxiang Chen
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China.
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, 169610, Singapore.
| |
Collapse
|
|
8
|
Okubo H, Ando H, Nakamura S, Takasaki Y, Ito K, Fukuo Y, Ikejima K, Isayama H. Real world data of cabozantinib in patients with hepatocellular carcinoma: Focusing on dose setting and modification. Cancer Med 2024; 13:e70222. [PMID: 39315523 PMCID: PMC11420626 DOI: 10.1002/cam4.70222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/25/2024] Open
Abstract
AIM To investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification. METHODS We retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients. RESULTS Sixteen patients received ≥40 mg (high-dose group), and 18 patients received 20 mg (low-dose group). Dose escalations were performed in 27.8% of the patients in the low-dose group. Although median duration of the first dose reduction or interruption in the low-dose group was twice that in the high-dose group (28 vs. 14 days, p < 0.001), there were no significant differences in the relative dose intensity (RDI) during 6 weeks, progression free survival (PFS), and overall survival (p = 0.162, p = 0.950, p = 0.817, respectively) between the two groups. Patients who received RDI during 6 weeks ≥33.4% showed a trend toward longer median PFS (p = 0.054). Each serum aldolase value during the 6 weeks was significantly correlated with the Ctrough at any point (r = 0.500, p < 0.001). In multivariate analyses, aldolase ≥8.7 U/L within 2 weeks was significantly associated with the very early dose reduction or interruption (odds ratio 20.0, p = 0.002). CONCLUSIONS An initial dose of 20 mg cabozantinib could be a safe option in Japanese patients. The serum aldolase value could be useful for making appropriate dose modifications of cabozantinib.
Collapse
Affiliation(s)
- Hironao Okubo
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hitoshi Ando
- Department of Cellular and Molecular Function Analysis, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
| | - Shunsuke Nakamura
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Yusuke Takasaki
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Koichi Ito
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Yuka Fukuo
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Kenichi Ikejima
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
9
|
Elshazly AM, Xu J, Melhem N, Abdulnaby A, Elzahed AA, Saleh T, Gewirtz DA. Is Autophagy Targeting a Valid Adjuvant Strategy in Conjunction with Tyrosine Kinase Inhibitors? Cancers (Basel) 2024; 16:2989. [PMID: 39272847 PMCID: PMC11394573 DOI: 10.3390/cancers16172989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs.
Collapse
Affiliation(s)
- Ahmed M. Elshazly
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA;
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Jingwen Xu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China;
| | - Nebras Melhem
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan;
| | - Alsayed Abdulnaby
- Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Aya A. Elzahed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, Hashemite University, Zarqa 13133, Jordan;
| | - David A. Gewirtz
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA;
| |
Collapse
|
|
10
|
Di T, Luo QY, Song JT, Yan XL, Zhang L, Pan WT, Guo Y, Lu FT, Sun YT, Xia ZF, Yang LQ, Qiu MZ, Yang DJ, Sun J. APG-1252 combined with Cabozantinib inhibits hepatocellular carcinoma by suppressing MEK/ERK and CREB/Bcl-xl pathways. Int Immunopharmacol 2024; 139:112615. [PMID: 39032475 DOI: 10.1016/j.intimp.2024.112615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/30/2024] [Accepted: 06/30/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND AND PURPOSE Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.
Collapse
Affiliation(s)
- Tian Di
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Qiu-Yun Luo
- Department of Clinical Research, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Jiang-Tao Song
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xiang-Lei Yan
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Center of Molecular Medicine, Stockholm, Sweden
| | - Lin Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Wen-Tao Pan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yu Guo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Fei-Teng Lu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yu-Ting Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Zeng-Fei Xia
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Li-Qiong Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Miao-Zhen Qiu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
| | - Da-Jun Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
| | - Jian Sun
- Department of Clinical Research, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China.
| |
Collapse
|
|
11
|
Mohan CD, Shanmugam MK, Gowda SGS, Chinnathambi A, Rangappa KS, Sethi G. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155379. [PMID: 38503157 DOI: 10.1016/j.phymed.2024.155379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
Collapse
Affiliation(s)
- Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226 001, India
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kanchugarakoppal S Rangappa
- Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| |
Collapse
|
|
12
|
Zarlashat Y, Abbas S, Ghaffar A. Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy. Cancers (Basel) 2024; 16:2034. [PMID: 38893154 PMCID: PMC11171154 DOI: 10.3390/cancers16112034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.
Collapse
Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| | - Shakil Abbas
- Gomal Center of Biotechnology and Biochemistry (GCBB), Gomal University, Dera Ismail Khan 29050, Pakistan;
| | - Abdul Ghaffar
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| |
Collapse
|
|
13
|
Lang D, Agarwal R, Goff LW, Heumann TR. Contemporary Systemic Therapy Approaches for Unresectable Hepatocellular Carcinoma. ADVANCES IN ONCOLOGY 2024; 4:233-246. [PMID: 38882259 PMCID: PMC11178263 DOI: 10.1016/j.yao.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Affiliation(s)
- Daenielle Lang
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rajiv Agarwal
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Laura W Goff
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thatcher R Heumann
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
14
|
Dolan M, Shi Y, Mastri M, Long MD, McKenery A, Hill JW, Vaghi C, Benzekry S, Barbi J, Ebos JM. A senescence-mimicking (senomimetic) VEGFR TKI side-effect primes tumor immune responses via IFN/STING signaling. Mol Cancer Ther 2024; 23:745113. [PMID: 38690835 PMCID: PMC11527799 DOI: 10.1158/1535-7163.mct-24-0139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 05/03/2024]
Abstract
Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) disrupt tumor angiogenesis but also have many unexpected side-effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence-markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ('senomimetic') VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. Using a live-cell sorting method to detect beta-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened interferon (IFN) signaling and increased expression of IFN-stimulated genes (ISGs). These ISG increases were under the control of the STimulator of INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host:tumor cell contact while tumors grown from SM+ cells were more sensitive to PD-L1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side-effects may help identify TKIs that uniquely 'prime' tumors for enhanced sensitivity to PD-L1 targeted agents.
Collapse
Affiliation(s)
- Melissa Dolan
- Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, NY, 14263. USA
| | - Yuhao Shi
- Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, NY, 14263. USA
| | - Michalis Mastri
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263. USA
| | - Mark D. Long
- Department of Bioinformatics and Statistics, Roswell Park Comprehensive Cancer Center Buffalo, NY, 14263. USA
| | - Amber McKenery
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263. USA
| | - James W. Hill
- Jacobs School of Medicine and Biomedical Sciences, SUNY at Buffalo, Buffalo, New York, 14263. USA
| | - Cristina Vaghi
- Inria Team MONC, Inria Bordeaux Sud-Ouest, Talence, France
- Computational Pharmacology and Clinical Oncology (COMPO), Inria Sophia Antipolis–Méditerranée, Cancer Research Center of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University UM105, 13385 Marseille, France
| | - Sebastien Benzekry
- Inria Team MONC, Inria Bordeaux Sud-Ouest, Talence, France
- Computational Pharmacology and Clinical Oncology (COMPO), Inria Sophia Antipolis–Méditerranée, Cancer Research Center of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University UM105, 13385 Marseille, France
| | - Joseph Barbi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263. USA
| | - John M.L. Ebos
- Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, NY, 14263. USA
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263. USA
- Department of Medicine, Roswell Park Comprehensive Cancer Center Buffalo, NY, 14263. USA
- Lead Contact
| |
Collapse
|
|
15
|
Li J, Wang X, Shi L, Liu B, Sheng Z, Chang S, Cai X, Shan G. A Mammalian Conserved Circular RNA CircLARP1B Regulates Hepatocellular Carcinoma Metastasis and Lipid Metabolism. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305902. [PMID: 37953462 PMCID: PMC10787103 DOI: 10.1002/advs.202305902] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/14/2023] [Indexed: 11/14/2023]
Abstract
Circular RNAs (circRNAs) have emerged as crucial regulators in physiology and human diseases. However, evolutionarily conserved circRNAs with potent functions in cancers are rarely reported. In this study, a mammalian conserved circRNA circLARP1B is identified to play critical roles in hepatocellular carcinoma (HCC). Patients with high circLARP1B levels have advanced prognostic stage and poor overall survival. CircLARP1B facilitates cellular metastatic properties and lipid accumulation through promoting fatty acid synthesis in HCC. CircLARP1B deficient mice exhibit reduced metastasis and less lipid accumulation in an induced HCC model. Multiple lines of evidence demonstrate that circLARP1B binds to heterogeneous nuclear ribonucleoprotein D (HNRNPD) in the cytoplasm, and thus affects the binding of HNRNPD to sensitive transcripts including liver kinase B1 (LKB1) mRNA. This regulation causes decreased LKB1 mRNA stability and lower LKB1 protein levels. Antisense oligodeoxynucleotide complementary to theHNRNPD binding sites in circLARP1B increases the HNRNPD binding to LKB1 mRNA. Through the HNRNPD-LKB1-AMPK pathway, circLARP1B promotes HCC metastasis and lipid accumulation. Results from AAV8-mediated hepatocyte-directed knockdown of circLARP1B or Lkb1 in mouse models also demonstrate critical roles of hepatocytic circLARP1B regulatory pathway in HCC metastasis and lipid accumulation, and indicate that circLARP1B may be potential target of HCC treatment.
Collapse
Affiliation(s)
- Jingxin Li
- Department of Laboratory MedicineThe First Affiliated Hospital of USTCThe CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Xiaolin Wang
- Department of Laboratory MedicineThe First Affiliated Hospital of USTCThe CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Liang Shi
- Department of General SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China
| | - Boqiang Liu
- Department of General SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China
| | - Zhiyong Sheng
- School of Life ScienceBengbu Medical CollegeBengbu233030China
| | - Shuhui Chang
- Department of Laboratory MedicineThe First Affiliated Hospital of USTCThe CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
| | - Xiujun Cai
- Department of General SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China
| | - Ge Shan
- Department of Laboratory MedicineThe First Affiliated Hospital of USTCThe CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei230027China
- Department of Pulmonary and Critical Care MedicineRegional Medical Center for National Institute of Respiratory DiseasesSir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China
| |
Collapse
|
|
16
|
Li D, Loriot Y, Burgoyne AM, Cleary JM, Santoro A, Lin D, Aix SP, Garrido-Laguna I, Sudhagoni R, Guo X, Andrianova S, Paulson S. Cabozantinib plus atezolizumab in previously untreated advanced hepatocellular carcinoma and previously treated gastric cancer and gastroesophageal junction adenocarcinoma: results from two expansion cohorts of a multicentre, open-label, phase 1b trial (COSMIC-021). EClinicalMedicine 2024; 67:102376. [PMID: 38204489 PMCID: PMC10776423 DOI: 10.1016/j.eclinm.2023.102376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/22/2023] [Accepted: 11/28/2023] [Indexed: 01/12/2024] Open
Abstract
Background Cabozantinib is approved for previously treated advanced hepatocellular carcinoma (aHCC) and has been investigated in gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Atezolizumab plus bevacizumab is approved for unresectable or metastatic HCC untreated with prior systemic therapy. We evaluated efficacy and safety of cabozantinib plus atezolizumab in aHCC previously untreated with systemic anticancer therapy or previously treated GC/GEJ. Methods COSMIC-021 (ClinicalTrials.gov, NCT03170960) is an open-label, phase 1b study in solid tumours with a dose-escalation stage followed by tumour-specific expansion cohorts, including aHCC (cohort 14) and GC/GEJ (cohort 15). Eligible patients were aged ≥18 years with measurable locally advanced, metastatic, or recurrent disease per RECIST version 1.1. Patients received oral cabozantinib 40 mg daily and intravenous atezolizumab 1200 mg once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1. Findings Patients were screened between February 14, 2019, and May 7, 2020, and 61 (30 aHCC, 31 GC/GEJ) were enrolled and received at least one dose of study treatment. Median duration of follow-up was 31.2 months (IQR 28.5-32.7) for aHCC and 30.4 months (28.7-31.9) for GC/GEJ. Objective response rate was 13% (4/30, 95% CI 4-31) for aHCC and 0% (95% CI 0-11) for GC/GEJ. Six (20%) aHCC patients and three (10%) GC/GEJ patients had treatment-related adverse events resulting in discontinuation of either study drug. Interpretation Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in aHCC previously untreated with systemic anticancer therapy. Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GC/GEJ. Funding Exelixis, Inc., Alameda, CA, USA.
Collapse
Affiliation(s)
- Daneng Li
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Yohann Loriot
- Department of Cancer Medicine, Gustave Roussy Institute, INSERM 981, University Paris-Saclay, Villejuif, France
| | | | - James M. Cleary
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Armando Santoro
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Rozzano, Italy
- Humanitas University, Pieve Emanuele, Italy
| | - Daniel Lin
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Santiago Ponce Aix
- Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit, Universidad Complutense and Ciberonc, Madrid, Spain
| | | | | | | | | | - Scott Paulson
- Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA
| |
Collapse
|
|
17
|
Maspero M, Yilmaz S, Cazzaniga B, Raj R, Ali K, Mazzaferro V, Schlegel A. The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence. JHEP Rep 2023; 5:100846. [PMID: 37771368 PMCID: PMC10523008 DOI: 10.1016/j.jhepr.2023.100846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 09/30/2023] Open
Abstract
The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.
Collapse
Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| |
Collapse
|
|
18
|
Jia W, Jin B, Xu W, Liu S, Mao X, Peng H, Zhang Y. pH-Responsive and Actively Targeted Metal-Organic Framework Structures for Multimodal Antitumor Therapy and Inhibition of Tumor Invasion and Metastasis. ACS APPLIED MATERIALS & INTERFACES 2023; 15:50069-50082. [PMID: 37871135 DOI: 10.1021/acsami.3c11909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Multimodal treatment is an important tool to overcome tumor drug resistance. The reactive oxygen species (ROS) generated by photodynamic therapy (PDT) can directly play a killing role on tumor cells, which has the advantages of repeatable treatment and no drug resistance. However, its therapeutic oxygen consumption and destruction of tumor microvessels lead to hypoxia in tumor tissues, and hypoxia leads to overexpression of the receptor tyrosine kinase (c-MET) and vascular endothelial growth factor receptor (VEGFR). Overexpression of these two receptors leads to increased tumor invasiveness and metastasis. The molecularly targeted drug cabozantinib (CAB) has multiple targets, including anti-c-MET and VEGFR, to inhibit the development of hepatocellular carcinoma (HCC). In this study, our team designed a pH-sensitive nanoparticle CAB/Ce6@ZIF-8@PEG-FA (CCZP) loaded with CAB and Ce6, which exerted a multimodal therapeutic effect of PDT and molecularly targeted therapy by laser irradiation, and the PDT-induced overexpression of MET and VEGFR could also be inhibited by the target of CAB, thus reducing the invasive tumor cells metastasis. In summary, CCZP gives full play to the advantages of both drugs, exerting multimodal treatment while reducing HCC invasion and metastasis, providing a safe, potential approach to clinical treatment.
Collapse
Affiliation(s)
- WeiLu Jia
- Medical School, Southeast University, Nanjing 210009, China
| | - Bin Jin
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250000, China
| | - WenJing Xu
- Medical School, Southeast University, Nanjing 210009, China
| | - ShiWei Liu
- Medical School, Southeast University, Nanjing 210009, China
| | - XinYu Mao
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Hao Peng
- Medical School, Southeast University, Nanjing 210009, China
| | - YeWei Zhang
- Medical School, Southeast University, Nanjing 210009, China
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China
| |
Collapse
|
|
19
|
Funato K, Miyake N, Sekiba K, Miyakawa Y, Seimiya T, Shibata C, Kishikawa T, Otsuka M. Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA. Hepatol Commun 2023; 7:e0313. [PMID: 37938099 PMCID: PMC10635605 DOI: 10.1097/hc9.0000000000000313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/18/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.
Collapse
Affiliation(s)
- Kazuyoshi Funato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nozomi Miyake
- Department of Gastroenterology, Graduate School of Medicine, Okayama University, Okayama, Japan
| | - Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yu Miyakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chikako Shibata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Gastroenterology, Graduate School of Medicine, Okayama University, Okayama, Japan
| |
Collapse
|
|
20
|
Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev 2023; 42:629-652. [PMID: 36729264 DOI: 10.1007/s10555-023-10084-4] [Citation(s) in RCA: 145] [Impact Index Per Article: 72.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/16/2023] [Indexed: 02/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.
Collapse
Affiliation(s)
- Yu Wang
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Baocheng Deng
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
| |
Collapse
|
|
21
|
Sanchez-Martin A, Sanchon-Sanchez P, Romero MR, Marin JJG, Briz O. Impact of tumor suppressor genes inactivation on the multidrug resistance phenotype of hepatocellular carcinoma cells. Biomed Pharmacother 2023; 165:115209. [PMID: 37499450 DOI: 10.1016/j.biopha.2023.115209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/13/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023] Open
Abstract
The response of advanced hepatocellular carcinoma (HCC) to pharmacological treatments is unsatisfactory and heterogeneous. Inactivation of tumor suppressor genes (TSGs) by genetic and epigenetic events is frequent in HCC. This study aimed at investigating the impact of frequently altered TSGs on HCC chemoresistance. TSG alterations were screened by in silico analysis of TCGA-LIHC database, and their relationship with survival was investigated. These TSGs were silenced in HCC-derived cell lines using CRISPR/Cas9. TLDA was used to determine the expression of a panel of 94 genes involved in the resistome. Drug sensitivity, cell proliferation, colony formation and cell migration were assessed. The in silico study revealed the down-regulation of frequently inactivated TSGs in HCC (ARID1A, PTEN, CDH1, and the target of p53, CDKN1A). The presence of TP53 and ARID1A variants and the low expression of PTEN and CDH1 correlated with a worse prognosis of HCC patients. In PLC/PRF/5 cells, ARID1A knockout (ARID1AKO) induced increased sensitivity to cisplatin, doxorubicin, and cabozantinib, without affecting other characteristics of malignancy. PTENKO and E-CadKO showed minimal changes in malignancy, resistome, and drug response. In p53KO HepG2 cells, enhanced malignant properties and higher resistance to cisplatin, doxorubicin, sorafenib, and regorafenib were found. This was associated with changes in the resistome. In conclusion, the altered expression and function of several TSGs are involved in the heterogeneity of HCC chemoresistance and other features of malignancy, contributing to the poor prognosis of these patients. Individual identification of pharmacological vulnerabilities is required to select the most appropriate treatment for each patient.
Collapse
Affiliation(s)
- Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
| | - Paula Sanchon-Sanchez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| |
Collapse
|
|
22
|
Lefebvre C, Pellizzari S, Bhat V, Jurcic K, Litchfield DW, Allan AL. Involvement of the AKT Pathway in Resistance to Erlotinib and Cabozantinib in Triple-Negative Breast Cancer Cell Lines. Biomedicines 2023; 11:2406. [PMID: 37760847 PMCID: PMC10525382 DOI: 10.3390/biomedicines11092406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/14/2023] [Accepted: 08/26/2023] [Indexed: 09/29/2023] Open
Abstract
Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that adaptive responses in regulatory kinase networks within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. We observed that erlotinib- or cabozantinib-resistant cell lines demonstrate enhanced cell proliferation, migration, invasion, and activation of EGFR or c-Met downstream signaling (respectively). Using a SILAC (Stable Isotope Labeling of Amino acids in Cell Culture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib or cabozantinib resistance on the phosphoproteome, proteome, and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozantinib resistance and confirmed the contribution of AKT1 to erlotinib resistance in TNBC-resistant cell lines.
Collapse
Affiliation(s)
- Cory Lefebvre
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Sierra Pellizzari
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Vasudeva Bhat
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Kristina Jurcic
- Department of Biochemistry, Western University, London, ON N6A 3K7, Canada; (K.J.); (D.W.L.)
| | - David W. Litchfield
- Department of Biochemistry, Western University, London, ON N6A 3K7, Canada; (K.J.); (D.W.L.)
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
| | - Alison L. Allan
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 5W9, Canada
| |
Collapse
|
|
23
|
Gorji L, Brown ZJ, Pawlik TM. Mutational Landscape and Precision Medicine in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4221. [PMID: 37686496 PMCID: PMC10487145 DOI: 10.3390/cancers15174221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, existing treatments carry a dismal prognosis, often plagued with high recurrence and mortality. For this reason, understanding the tumor microenvironment and mutational pathophysiology has become the center of investigation for disease control. The use of precision medicine and genetic analysis can supplement current treatment modalities to promote individualized management of HCC. In the search for personalized medicine, tools such as next-generation sequencing have been used to identify unique tumor mutations and improve targeted therapies. Furthermore, investigations are underway for specific HCC biomarkers to augment the diagnosis of malignancy, the prediction of whether the tumor environment is amenable to available therapies, the surveillance of treatment response, the monitoring for disease recurrence, and even the identification of novel therapeutic opportunities. Understanding the mutational landscape and biomarkers of the disease is imperative for tailored management of the malignancy. In this review, we summarize the molecular targets of HCC and discuss the current role of precision medicine in the treatment of HCC.
Collapse
Affiliation(s)
- Leva Gorji
- Department of Surgery, Kettering Health Dayton, Dayton, OH 45405, USA;
| | - Zachary J. Brown
- Department of Surgery, Division of Surgical Oncology, New York University—Long Island, Mineola, NY 11501, USA;
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus, OH 43210, USA
| |
Collapse
|
|
24
|
Jeon Y, Kim T, Kwon H, Kim JK, Park YT, Ham J, Kim YJ. Cannabidiol Enhances Cabozantinib-Induced Apoptotic Cell Death via Phosphorylation of p53 Regulated by ER Stress in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3987. [PMID: 37568803 PMCID: PMC10417827 DOI: 10.3390/cancers15153987] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Cannabidiol (CBD), a primary constituent in hemp and cannabis, exerts broad pharmacological effects against various diseases, including cancer. Additionally, cabozantinib, a potent multi-kinase inhibitor, has been approved for treating patients with advanced hepatocellular carcinoma (HCC). Recently, there has been an increase in research on combination therapy using cabozantinib to improve efficacy and safety when treating patients. Here, we investigated the effect of a combination treatment of cabozantinib and CBD on HCC cells. CBD treatment enhanced the sensitivity of HCC cells to cabozantinib-mediated anti-cancer activity by increasing cytotoxicity and apoptosis. Phospho-kinase array analysis demonstrated that the apoptotic effect of the combination treatment was mainly related to p53 phosphorylation regulated by endoplasmic reticulum (ER) stress when compared to other kinases. The inhibition of p53 expression and ER stress suppressed the apoptotic effect of the combination treatment, revealing no changes in the expression of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, or cleaved caspase-9. Notably, the effect of the combination treatment was not associated with cannabinoid receptor 1 (CNR1) and the CNR2 signaling pathways. Our findings suggest that the combination therapy of cabozantinib and CBD provides therapeutic efficacy against HCC.
Collapse
Affiliation(s)
- Youngsic Jeon
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| | - Taejung Kim
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Hyukjoon Kwon
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| | | | - Young-Tae Park
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| | - Jungyeob Ham
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
- NeoCannBio Co., Ltd., Seoul 02792, Republic of Korea;
| | - Young-Joo Kim
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; (Y.J.); (T.K.); (H.K.); (Y.-T.P.)
| |
Collapse
|
|
25
|
Kuzuya T, Kawabe N, Ariga M, Ohno E, Funasaka K, Nagasaka M, Nakagawa Y, Miyahara R, Shibata T, Takahara T, Kato Y, Hirooka Y. Clinical Outcomes of Cabozantinib in Patients Previously Treated with Atezolizumab/Bevacizumab for Advanced Hepatocellular Carcinoma-Importance of Good Liver Function and Good Performance Status. Cancers (Basel) 2023; 15:2952. [PMID: 37296914 PMCID: PMC10251863 DOI: 10.3390/cancers15112952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/16/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child-Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child-Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child-Pugh A) and are in good general condition (ECOG-PS 0/1).
Collapse
Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Naoto Kawabe
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Mizuki Ariga
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Eizaburo Ohno
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Kohei Funasaka
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Mitsuo Nagasaka
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Yoshihito Nakagawa
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Ryoji Miyahara
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Tomoyuki Shibata
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| | - Takeshi Takahara
- Department of Surgery, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (T.T.)
| | - Yutaro Kato
- Department of Surgery, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (T.T.)
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Aichi, Japan; (N.K.); (M.A.); (E.O.); (K.F.); (M.N.); (Y.N.); (R.M.); (T.S.)
| |
Collapse
|
|
26
|
Samavarchi Tehrani S, Esmaeili F, Shirzad M, Goodarzi G, Yousefi T, Maniati M, Taheri-Anganeh M, Anushiravani A. The critical role of circular RNAs in drug resistance in gastrointestinal cancers. Med Oncol 2023; 40:116. [PMID: 36917431 DOI: 10.1007/s12032-023-01980-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 02/20/2023] [Indexed: 03/16/2023]
Abstract
Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.
Collapse
Affiliation(s)
- Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Golnaz Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tooba Yousefi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Maniati
- Department of English, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
27
|
Butt NUH, Baytas SN. Advancements in Hepatocellular Carcinoma: Potential Preclinical Drugs and their Future. Curr Pharm Des 2023; 29:2-14. [PMID: 36529919 DOI: 10.2174/1381612829666221216114350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 10/12/2022] [Accepted: 10/27/2022] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the foremost causes of tumor-affiliated demises globally. The HCC treatment has undergone numerous developments in terms of both drug and non-drug treatments. The United States Food and Drug Administration (FDA) has authorized the usage of a variety of drugs for the treatment of HCC in recent years, involving multi-kinase inhibitors (lenvatinib, regorafenib, ramucirumab, and cabozantinib), immune checkpoint inhibitors (ICIs) (pembrolizumab and nivolumab), and combination therapies like atezolizumab along with bevacizumab. There are currently over a thousand ongoing clinical and preclinical studies for novel HCC drugs, which portrays a competent setting in the field. This review discusses the i. FDA-approved HCC drugs, their molecular targets, safety profiles, and potential disadvantages; ii. The intrial agents/drugs, their molecular targets, and possible benefits compared to alternatives, and iii. The current and future status of potential preclinical drugs with novel therapeutic targets for HCC. Consequently, existing drug treatments and novel strategies with their balanced consumption could ensure a promising future for a universal remedy of HCC in the near future.
Collapse
Affiliation(s)
- Noor-Ul-Huda Butt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkiye
| | - Sultan Nacak Baytas
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkiye
| |
Collapse
|
|
28
|
Wang J, Wu R, Sun JY, Lei F, Tan H, Lu X. An overview: Management of patients with advanced hepatocellular carcinoma. Biosci Trends 2022; 16:405-425. [PMID: 36476621 DOI: 10.5582/bst.2022.01109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) has constituted a significant health burden worldwide, and patients with advanced HCC, which is stage C as defined by the Barcelona Clinic Liver Cancer staging system, have a poor overall survival of 6-8 months. Studies have indicated the significant survival benefit of treatment based on sorafenib, lenvatinib, or atezolizumab-bevacizumab with reliable safety. In addition, the combination of two or more molecularly targeted therapies (first- plus second-line) has become a hot topic recently and is now being extensively investigated in patients with advanced HCC. In addition, a few biomarkers have been investigated and found to predict drug susceptibility and prognosis, which provides an opportunity to evaluate the clinical benefits of current therapies. In addition, many therapies other than tyrosine kinase inhibitors that might have additional survival benefits when combined with other therapeutic modalities, including immunotherapy, transarterial chemoembolization, radiofrequency ablation, hepatectomy, and chemotherapy, have also been examined. This review provides an overview on the current understanding of disease management and summarizes current challenges with and future perspectives on advanced HCC.
Collapse
Affiliation(s)
- Jincheng Wang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.,Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Japan
| | - Rui Wu
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin-Yu Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feifei Lei
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
29
|
Impact of Cabozantinib Exposure on Proteinuria and Muscle Toxicity in Patients with Unresectable Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2022; 15:ph15121460. [PMID: 36558911 PMCID: PMC9783864 DOI: 10.3390/ph15121460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/15/2022] [Accepted: 11/24/2022] [Indexed: 11/27/2022] Open
Abstract
This prospective study investigated the impact of cabozantinib exposure on proteinuria and muscle toxicity, in a cohort of 14 Japanese patients with unresectable hepatocellular carcinoma (uHCC). We measured the trough concentration of cabozantinib (Ctrough) weekly for 6 weeks after starting treatment. Although the initial dose was less than 60 mg in most cases, dose interruption occurred in 79%, primarily because of proteinuria and/or malaise. The median and coefficient of variation of maximum Ctrough at 7−42 d were 929.0 ng/mL and 59.2%, respectively. The urinary protein-to-creatinine ratio (UPCR), serum creatine kinase, and serum aldolase values were all significantly elevated following treatment. Moreover, maximum changes in serum creatine kinase and aldolase were significantly associated with maximum Ctrough (r = 0.736, p < 0.01; r = 0.798, p < 0.001; respectively). Receiver operating characteristic (ROC) curve analysis showed that changes in serum creatine kinase ≥70.5 U/L and aldolase ≥6.1 U/L from baseline relatively accurately predicted inclusion in the high-maximum Ctrough (≥929.0 ng/mL) group, with an area under the ROC of 0.929 and 0.833, respectively. Measurement of serum creatine kinase and aldolase may increase the clinical usefulness of cabozantinib treatment for uHCC and help alleviate difficulties with dose adjustments.
Collapse
|
|
30
|
Tang Y, Zhang H, Chen L, Zhang T, Xu N, Huang Z. Identification of Hypoxia-Related Prognostic Signature and Competing Endogenous RNA Regulatory Axes in Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:13590. [PMID: 36362375 PMCID: PMC9658439 DOI: 10.3390/ijms232113590] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 11/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common type of liver cancer and one of the highly lethal diseases worldwide. Hypoxia plays an important role in the development and prognosis of HCC. This study aimed to construct a new hypoxia-related prognosis signature and investigate its potential ceRNA axes in HCC. RNA profiles and hypoxia genes were downloaded, respectively, from the Cancer Genome Atlas hepatocellular carcinoma database and Gene Set Enrichment Analysis website. Cox regression analyses were performed to select the prognostic genes and construct the risk model. The ENCORI database was applied to build the lncRNA-miRNA-mRNA prognosis-related network. The TIMER and CellMiner databases were employed to analyze the association of gene expression in ceRNA with immune infiltration and drug sensitivity, respectively. Finally, the co-expression analysis was carried out to construct the potential lncRNA/miRNA/mRNA regulatory axes. We obtained a prognostic signature including eight hypoxia genes (ENO2, KDELR3, PFKP, SLC2A1, PGF, PPFIA4, SAP30, and TKTL1) and further established a hypoxia-related prognostic ceRNA network including 17 lncRNAs, six miRNAs, and seven mRNAs for hepatocellular carcinoma. Then, the analysis of immune infiltration and drug sensitivity showed that gene expression in the ceRNA network was significantly correlated with the infiltration abundance of multiple immune cells, the expression level of immune checkpoints, and drug sensitivity. Finally, we identified three ceRNA regulatory axes (SNHG1/miR-101-3p/PPFIA4, SNHG1/miR-101-3p/SAP30, and SNHG1/miR-101-3p/TKTL1) associated with the progression of HCC under hypoxia. Here, we constructed a prognosis gene signature and a ceRNA network related to hypoxia for hepatocellular carcinoma. Among the ceRNA network, six highly expressed lncRNAs (AC005540.1, AC012146.1, AC073529.1, AC090772.3, AC138150.2, AL390728.6) and one highly expressed mRNA (PPFIA4) were the potential biomarkers of hepatocellular carcinoma which we firstly reported. The three predicted hypoxia-related regulatory axes may play a vital role in the progression of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Yulai Tang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China
- The First Clinical Medical College, Guangdong Medical University, Dongguan 523808, China
| | - Hua Zhang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Lingli Chen
- The First Clinical Medical College, Guangdong Medical University, Dongguan 523808, China
| | - Taomin Zhang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Na Xu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
| | - Zunnan Huang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan 523808, China
- Marine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang 524023, China
| |
Collapse
|
|
31
|
Czogalla B, Dötzer K, Sigrüner N, von Koch FE, Brambs CE, Anthuber S, Frangini S, Burges A, Werner J, Mahner S, Mayer B. Combined Expression of HGFR with Her2/neu, EGFR, IGF1R, Mucin-1 and Integrin α2β1 Is Associated with Aggressive Epithelial Ovarian Cancer. Biomedicines 2022; 10:2694. [PMID: 36359213 PMCID: PMC9687566 DOI: 10.3390/biomedicines10112694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/15/2022] [Accepted: 10/21/2022] [Indexed: 09/10/2023] Open
Abstract
Hepatocyte growth factor receptor (HGFR), also known as c-mesenchymal-epithelial transition factor (c-MET), plays a crucial role in the carcinogenesis of epithelial ovarian cancer (EOC). In contrast, the mechanisms contributing to aberrant expression of HGFR in EOC are not fully understood. In the present study, the expression of HGFR with its prognostic and predictive role was evaluated immunohistochemically in a cohort of 42 primary ovarian cancer patients. Furthermore, we analyzed the dual expression of HGFR and other druggable biomarkers. In the multivariate Cox regression analysis, high HGFR expression was identified as an independent prognostic factor for a shorter progression-free survival (PFS) (hazard ratio (HR) 2.99, 95% confidence interval (CI95%) 1.01-8.91, p = 0.049) and overall survival (OS) (HR 5.77, CI95% 1.56-21.34, p = 0.009). In addition, the combined expression of HGFR, human epidermal growth factor receptor 2 (Her2/neu), epithelial growth factor receptor (EGFR), insulin-like growth factor 1 (IGF1R), Mucin-1 and Integrin α2β1 further significantly impaired PFS, platinum-free interval (PFI) and OS. Protein co-expression analyses were confirmed by transcriptomic data in a large, independent cohort of patients. In conclusion, new biomarker-directed treatment targets were identified to fight poor prognosis of primary EOC.
Collapse
Affiliation(s)
- Bastian Czogalla
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Katharina Dötzer
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Nicole Sigrüner
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Franz Edler von Koch
- Gynecology and Obstetrics Clinic, Klinikum Dritter Orden, Menzinger Straße 44, 80638 Munich, Germany
| | - Christine E. Brambs
- Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Straße 22, 81675 Munich, Germany
| | - Sabine Anthuber
- Department of Obstetrics and Gynecology, Starnberg Hospital, Oßwaldstraße 1, 82319 Starnberg, Germany
| | - Sergio Frangini
- Department of Obstetrics and Gynecology, Munich Clinic Harlaching, Sanatoriumsplatz 2, 81545 Munich, Germany
| | - Alexander Burges
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Jens Werner
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Barbara Mayer
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| |
Collapse
|
|
32
|
Storandt MH, Gile JJ, Palmer ME, Zemla TJ, Ahn DH, Bekaii-Saab TS, Jin Z, Tran NH, Mahipal A. Cabozantinib Following Immunotherapy in Patients with Advanced Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14215173. [PMID: 36358592 PMCID: PMC9657200 DOI: 10.3390/cancers14215173] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan-Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3-3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3-14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.
Collapse
Affiliation(s)
| | | | | | - Tyler J. Zemla
- Department of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN 55905, USA
| | - Daniel H. Ahn
- Department of Hematology/Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
| | | | - Zhaohui Jin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Nguyen H. Tran
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH 44106, USA
- Correspondence: ; Tel.: +1-216-844-3951; Fax: +1-216-844-5234
| |
Collapse
|
|
33
|
Hu B, Zou T, Qin W, Shen X, Su Y, Li J, Chen Y, Zhang Z, Sun H, Zheng Y, Wang CQ, Wang Z, Li TE, Wang S, Zhu L, Wang X, Fu Y, Ren X, Dong Q, Qin LX. Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3-ABCB1 Signaling in Hepatocellular Carcinoma. Cancer Res 2022; 82:3845-3857. [PMID: 36066408 PMCID: PMC9574378 DOI: 10.1158/0008-5472.can-21-4140] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 07/18/2022] [Accepted: 08/29/2022] [Indexed: 01/07/2023]
Abstract
UNLABELLED Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR-STAT3-ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft-dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR-STAT3-ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease. SIGNIFICANCE HCC cells acquire resistance to lenvatinib by activating the EGFR-STAT3-ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.
Collapse
Affiliation(s)
- Beiyuan Hu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Tiantian Zou
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Wei Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaotian Shen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yinghan Su
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jianhua Li
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yang Chen
- Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ze Zhang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Haoting Sun
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chao-Qun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Tian-En Li
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Shun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Le Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xufeng Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yan Fu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xudong Ren
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| |
Collapse
|
|
34
|
Mossenta M, Busato D, Dal Bo M, Macor P, Toffoli G. Novel Nanotechnology Approaches to Overcome Drug Resistance in the Treatment of Hepatocellular Carcinoma: Glypican 3 as a Useful Target for Innovative Therapies. Int J Mol Sci 2022; 23:10038. [PMID: 36077433 PMCID: PMC9456072 DOI: 10.3390/ijms231710038] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/30/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most lethal tumor, with a 5-year survival rate of 18%. Early stage HCC is potentially treatable by therapies with curative intent, whereas chemoembolization/radioembolization and systemic therapies are the only therapeutic options for intermediate or advanced HCC. Drug resistance is a critical obstacle in the treatment of HCC that could be overcome by the use of targeted nanoparticle-based therapies directed towards specific tumor-associated antigens (TAAs) to improve drug delivery. Glypican 3 (GPC3) is a member of the glypican family, heparan sulfate proteoglycans bound to the cell surface via a glycosylphosphatidylinositol anchor. The high levels of GPC3 detected in HCC and the absence or very low levels in normal and non-malignant liver make GPC3 a promising TAA candidate for targeted nanoparticle-based therapies. The use of nanoparticles conjugated with anti-GPC3 agents may improve drug delivery, leading to a reduction in severe side effects caused by chemotherapy and increased drug release at the tumor site. In this review, we describe the main clinical features of HCC and the common treatment approaches. We propose the proteoglycan GPC3 as a useful TAA for targeted therapies. Finally, we describe nanotechnology approaches for anti-GPC3 drug delivery systems based on NPs for HCC treatment.
Collapse
Affiliation(s)
- Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Paolo Macor
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| |
Collapse
|
|
35
|
Laface C, Fedele P, Maselli FM, Ambrogio F, Foti C, Molinari P, Ammendola M, Lioce M, Ranieri G. Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities. Cancers (Basel) 2022; 14:4028. [PMID: 36011021 PMCID: PMC9406380 DOI: 10.3390/cancers14164028] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 12/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.
Collapse
Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, BR, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, BR, Italy
| | | | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Caterina Foti
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | | | - Michele Ammendola
- Department of Health Science, General Surgery, Medicine School of Germaneto, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marco Lioce
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
| | | |
Collapse
|
|
36
|
Lee SY, Park LM, Oh YJ, Choi DH, Lee DW. High Throughput 3D Cell Migration Assay Using Micropillar/Microwell Chips. Molecules 2022; 27:molecules27165306. [PMID: 36014542 PMCID: PMC9416089 DOI: 10.3390/molecules27165306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/08/2022] [Accepted: 08/16/2022] [Indexed: 11/28/2022] Open
Abstract
The 3D cell migration assay was developed for the evaluation of drugs that inhibit cell migration using high throughput methods. Wound-healing assays have commonly been used for cell migration assays. However, these assays have limitations in mimicking the in vivo microenvironment of the tumor and measuring cell viability for evaluation of cell migration inhibition without cell toxicity. As an attempt to manage these limitations, cells were encapsulated with Matrigel on the surface of the pillar, and an analysis of the morphology of cells attached to the pillar through Matrigel was performed for the measurement of cell migration. The micropillar/microwell chips contained 532 pillars and wells, which measure the migration and viability of cells by analyzing the roundness and size of the cells, respectively. Cells seeded in Matrigel have a spherical form. Over time, cells migrate through the Matrigel and attach to the surface of the pillar. Cells that have migrated and adhered have a diffused shape that is different from the initial spherical shape. Based on our analysis of the roundness of the cells, we were able to distinguish between the diffuse and spherical shapes. Cells in Matrigel on the pillar that were treated with migration-inhibiting drugs did not move to the surface of the pillar and remained in spherical forms. During the conduct of experiments, 70 drugs were tested in single chips and migration-inhibiting drugs without cell toxicity were identified. Conventional migration assays were performed using transwell for verification of the four main migration-inhibiting drugs found on the chip.
Collapse
Affiliation(s)
- Sang-Yun Lee
- Department of Biomedical Engineering, Gachon University, Seongnam 13120, Korea
| | - Lily M. Park
- Cytek Biosciences, 47215 Lakeview Blvd, Fremont, CA 95348, USA
| | - Yoo Jung Oh
- Department of Biomedical Engineering, Konyang University, Daejeon 35365, Korea
| | - Dong Hyuk Choi
- Department of Biomedical Engineering, Konyang University, Daejeon 35365, Korea
- Correspondence: (D.H.C.); (D.W.L.)
| | - Dong Woo Lee
- Department of Biomedical Engineering, Gachon University, Seongnam 13120, Korea
- Medical & Bio Decision (MBD), Suwon 16229, Korea
- Correspondence: (D.H.C.); (D.W.L.)
| |
Collapse
|
|
37
|
Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells. Int J Mol Sci 2022; 23:ijms23169108. [PMID: 36012373 PMCID: PMC9409026 DOI: 10.3390/ijms23169108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
Collapse
|
|
38
|
Feng MY, Chan LL, Chan SL. Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond. Curr Oncol 2022; 29:5489-5507. [PMID: 36005172 PMCID: PMC9406660 DOI: 10.3390/curroncol29080434] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.
Collapse
Affiliation(s)
- Maple Ye Feng
- Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Landon L. Chan
- Department of Oncology, Princess Margaret Hospital, Hong Kong, China
| | - Stephen Lam Chan
- Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
39
|
Zhang Z, Li D, Yun H, Tong J, Liu W, Chai K, Zeng T, Gao Z, Xie Y. Opportunities and challenges of targeting c-Met in the treatment of digestive tumors. Front Oncol 2022; 12:923260. [PMID: 35978812 PMCID: PMC9376446 DOI: 10.3389/fonc.2022.923260] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.
Collapse
Affiliation(s)
- Zhengchao Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Dong Li
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Jie Tong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Wei Liu
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Keqiang Chai
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Tongwei Zeng
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Zhenghua Gao
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
| | - Yongqiang Xie
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
| |
Collapse
|
|
40
|
Jiang T, Liu Z, Liu W, Chen J, Zheng Z, Duan M. The Conformational Transition Pathways and Hidden Intermediates in DFG-Flip Process of c-Met Kinase Revealed by Metadynamics Simulations. J Chem Inf Model 2022; 62:3651-3663. [PMID: 35848778 DOI: 10.1021/acs.jcim.2c00770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Protein kinases intrinsically translate their conformations between active and inactive states, which is key to their enzymatic activities. The conformational flipping of the three-residue conservative motif, Asp-Phe-Gly (DFG), is crucial for many kinases' biological functions. Obtaining a detailed demonstration of the DFG flipping process and its corresponding dynamical and thermodynamical features could broaden our understanding of kinases' conformation-activity relationship. In this study, we employed metadynamics simulation, a widely used enhanced sampling technique, to analyze the conformational transition pathways of the DFG flipping for the c-Met kinase. The corresponding free energy landscape suggested two distinct transition pathways between the "DFG-in" and "DFG-out" states of the DFG-flip from c-Met. On the basis of the orientation direction of the F1223 residue, we correspondingly named the two pathways the "DFG-up" path, featuring forming a commonly discovered "DFG-up" transition state, and the "DFG-down" path, a unique transition pathway with F1223 rotating along the opposite direction away from the hydrophobic cavity. The free energies along the two pathways were then calculated using the Path Collective Variable (PCV) metadynamics simulation. The simulation results showed that, though having similar free energy barriers, the free energy cuve for the DFG-down path suggested a two-step conformational transition mechanism, while that for the DFG-up path showed the one-step transition feature. The c-Met DFG flipping mechanism and the new intermediate state discovered in this work could provide a deeper understanding of the conformation-activity relationship for c-Met and, possibly, reveal a new conformational state as the drug target for c-Met and other similar kinases.
Collapse
Affiliation(s)
- Tao Jiang
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, P. R. China
| | - Zhenhao Liu
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, P. R. China
| | - Wenlang Liu
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, P. R. China
| | - Jiawen Chen
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, P. R. China
| | - Zheng Zheng
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, P. R. China
| | - Mojie Duan
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, P. R. China
| |
Collapse
|
|
41
|
Awasthi N, Schwarz MA, Zhang C, Klinz SG, Meyer-Losic F, Beaufils B, Thiagalingam A, Schwarz RE. Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy. Mol Cancer Ther 2022; 21:1149-1159. [PMID: 35500018 PMCID: PMC9377761 DOI: 10.1158/1535-7163.mct-21-0860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/22/2022] [Accepted: 04/28/2022] [Indexed: 01/07/2023]
Abstract
Gastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.
Collapse
Affiliation(s)
- Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Margaret A. Schwarz
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
- Department of Pediatrics, Indiana University School of Medicine, South Bend, Indiana
| | - Changhua Zhang
- Department of Gastrointestinal Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Guangming, Shenzhen, China
| | | | | | | | | | - Roderich E. Schwarz
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
- Roswell Park Comprehensive Cancer Center, Buffalo, New York
| |
Collapse
|
|
42
|
Esteban-Fabró R, Willoughby CE, Piqué-Gili M, Montironi C, Abril-Fornaguera J, Peix J, Torrens L, Mesropian A, Balaseviciute U, Miró-Mur F, Mazzaferro V, Pinyol R, Llovet JM. Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma. Clin Cancer Res 2022; 28:2449-2460. [PMID: 35302601 PMCID: PMC9167725 DOI: 10.1158/1078-0432.ccr-21-2517] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 01/28/2022] [Accepted: 03/16/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Immune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. EXPERIMENTAL DESIGN C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival. RESULTS The combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P < 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P < 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P < 0.01) and memory/effector T cells (P < 0.05), while lowering the neutrophil-to-lymphocyte ratio (P < 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes. CONCLUSIONS Cabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.
Collapse
Affiliation(s)
- Roger Esteban-Fabró
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Catherine E. Willoughby
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Marta Piqué-Gili
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Carla Montironi
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Jordi Abril-Fornaguera
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Judit Peix
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Laura Torrens
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Agavni Mesropian
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Ugne Balaseviciute
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Francesc Miró-Mur
- Systemic Autoimmune Diseases, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Catalonia, Spain
| | - Vincenzo Mazzaferro
- Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Surgery, Milan, Italy
- University of Milan, Department of Oncology, Milan, Italy
| | - Roser Pinyol
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Josep M. Llovet
- Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
- Corresponding author: Contact information: Professor Josep M. Llovet, Translational Research in Hepatic Oncology Laboratory, Liver Unit, IDIBAPS-Hospital Clínic, University of Barcelona, C/Rosselló 153, 08036, Barcelona, Catalonia, Spain. Tel: +34 93 227 9155.
| |
Collapse
|
|
43
|
Azhie A, Grant RC, Herman M, Wang L, Knox JJ, Bhat M. Phase II clinical trial of cabozantinib for the treatment of recurrent hepatocellular carcinoma after liver transplantation. Future Oncol 2022; 18:2173-2191. [PMID: 35287469 DOI: 10.2217/fon-2021-1635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Recurrent hepatocellular carcinoma (HCC) develops in 15-20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatments and no prior treatment with cabozantinib. In this study, 60 mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8 weeks to evaluate response. The primary end point of this study will be the disease control rate at 4 months after treatment. The secondary end points will be overall survival, progression-free survival and safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3 years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.
Collapse
Affiliation(s)
- Amirhossein Azhie
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, M5G 2N2, Canada
| | - Robert C Grant
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Michael Herman
- Oakville Trafalgar Memorial Hospital, Oakville, Ontario, L6M 0L8, Canada
| | - Lisa Wang
- Biostatistics Division, Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 2M9, Canada
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, M5G 2N2, Canada
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Toronto, Ontario, M5S 1A8, Canada
| |
Collapse
|
|
44
|
Role of Anti-Angiogenic Factors in the Pathogenesis of Breast Cancer: A Review of Therapeutic Potential. Pathol Res Pract 2022; 236:153956. [DOI: 10.1016/j.prp.2022.153956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/06/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022]
|
|
45
|
Production and Conjugation of Truncated Recombinant Diphtheria Toxin to VEGFR-2 Specific Nanobody and Evaluation of its Cytotoxic Effect on PC-3 Cell Line. Mol Biotechnol 2022; 64:1218-1226. [PMID: 35478310 DOI: 10.1007/s12033-022-00485-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 03/25/2022] [Indexed: 10/18/2022]
Abstract
Immunotoxins have represented a great potency in targeted therapeutics to encounter tumors. They consist of a protein toxin conjugated to a targeting moiety, which recognizes a specific antigen on surface of cancer cells and accordingly induces cell death by toxin segment. The targeting part could be a nanobody, which is a group of antibodies composed of an only functional single variable heavy chain (VHH).Therefore, this study was done to produce an immunotoxin (VGRNb-DT) by chemical conjugation of a truncated diphtheria toxin moiety to an anti-vascular endothelial growth factor receptor 2(VEGFR-2) nanobody, and to identify effectiveness of immunotoxin in recognizing the VEGFR-2- positive cancer cells and inhibiting cell growth and survival. Diphtheria toxin was expressed and purified by nickel affinity chromatography, and accordingly, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis confirmed its expression. Function of heterobifunctional crosslinkers, Sulfo-SMCC (sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate), and SATP (N-succinimidyl-S- acetylthiopropionate) for bioconjugation purposes was acknowledged by cation exchange high-performance liquid chromatography (HPLC). Cytotoxicity of immunotoxin was evaluated on the VEGFR-2 positive PC-3 cell line by MTT assay. Overexpression of VEGFR-2 in the PC-3 cell line allowed immunotoxin to recognize them by anti-VEGFR-2 nanobodies. The concentrations above 5 μg/ml represented a significant decrease in cell survival rate in PC-3 cells compared to HEK293 cells (VEGFR-2 negative cells) as controls.VGRNb-DT demonstrated a successful bioconjugation; furthermore, variable concentrations were correlated with cell death in prostate cancer PC-3 cells.
Collapse
|
|
46
|
Kasai S, Kuwayama N, Motoo Y, Kawashima A, Matsumoto K, Yano S, Matsushima K, Yasumoto K. Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer. Biochem Biophys Res Commun 2022; 600:80-86. [DOI: 10.1016/j.bbrc.2022.02.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 12/15/2022]
|
|
47
|
Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution. Int J Mol Sci 2022; 23:ijms23073830. [PMID: 35409190 PMCID: PMC8998551 DOI: 10.3390/ijms23073830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 02/01/2023] Open
Abstract
The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients’ prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones’ survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host’s immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.
Collapse
|
|
48
|
Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
Collapse
Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
| |
Collapse
|
|
49
|
The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications. Cancers (Basel) 2022; 14:cancers14040940. [PMID: 35205692 PMCID: PMC8870127 DOI: 10.3390/cancers14040940] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have paradoxical implications. While acting as a potent tumor suppressor pathway in the early stages of malignancy, TGF-β diverts to a promoter of tumor progression in the late stages, reflecting its bright and dark natures, respectively. Within this context, targeting TGF-β represents a promising therapeutic option for HCC treatment. We discuss here the molecular properties of TGF-β signaling in HCC, attempting to provide an overview of its effects on tumor cells and the stroma. We also seek to evaluate the dysregulation mechanisms that mediate the functional switch of TGF-β from a tumor suppressor to a pro-tumorigenic signal. Finally, we reconcile its biphasic nature with the therapeutic implications. Abstract Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.
Collapse
|
|
50
|
Marin JJG, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Sanchez-Martin A, Fabris L, Briz O. Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems. Semin Liver Dis 2022; 42:87-103. [PMID: 34544160 DOI: 10.1055/s-0041-1735631] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarterial chemoembolization. The only therapeutic option for most patients with advanced HCC is systemic pharmacological treatments based on tyrosine kinase inhibitors (TKIs) and immunotherapy. Available drugs only slightly increase survival, as tumor cells possess additive and synergistic mechanisms of pharmacoresistance (MPRs) prior to or enhanced during treatment. Understanding the molecular basis of MPRs is crucial to elucidate the genetic signature underlying HCC resistome. This will permit the selection of biomarkers to predict drug treatment response and identify tumor weaknesses in a personalized and dynamic way. In this article, we have reviewed the role of MPRs in current first-line drugs and the combinations of immunotherapeutic agents with novel TKIs being tested in the treatment of advanced HCC.
Collapse
Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.,Department of Internal Medicine, Yale Liver Center (YLC), School of Medicine, Yale University New Haven, Connecticut
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| |
Collapse
|